Some general considerations relating to drug formulation are provided herein in order to understand the constraints applicable to the formulation of drugs which have low solubility in water and at the same time the kind of pharmaceutical solid formulations to which the present invention relates.
Tablets and capsules are generally unsuitable for administering high doses of biologically active ingredients since individual large dosage forms are difficult to swallow or necessitate the administration of several tablets or capsules at a time, leading to impaired patient compliance.
Hard gelatin capsules are known as a conventional pharmaceutical dosage form. Their sizes have been standard since the start of industrial manufacture of drug compositions, ranging from 5 (corresponding to a volume of 0.13 ml) up to 000 (corresponding to a volume of 1.36 ml). Thus, when a large amount of ingredient is required for each dosage unit, depending on the bulk density of the formulation, it may be necessary to use large size capsules which are too large to swallow or, even worse, a size 000 capsule may be too small to receive the said amount. Pellets and granules have been filled into hard gelatin capsules to be used as conventional or controlled release dosage forms, however the latter are rather difficult to manufacture.
The concept of tabletting coated active ingredient particles is therefore of major interest. Attempts have been made to produce tablets comprising microcapsules because of the advantages resulting from the microencapsulated substance being protected from external influences and vice-versa, e.g. increased stability, reduced chances of irritations or undesirable reactions with other components in a mixture, ability to mask unpleasant tastes and smells, etc. However, compaction of coated beads or pellets for making tablets encounters many difficulties and problems. As is well known in the pharmaceutical industry, beads or pellets are quite distinguishable from granules. Beads can be defined as small, free-flowing spherical or sphere-like particulates manufactured by pelletization, i.e. the agglomeration of fine powders or granules of drug substances and excipients using appropriate processing equipment. As opposed to the process of granulation, the production of beads by pelletization results in a larger average size and a narrower size-range distribution.
Another difficult problem is the formulation of drugs having low or very low water-solubility into solid dosage forms for immediate release. Few solutions to this problem have been disclosed in the art. For instance, U.S. Patent Publication No. 2001/0048946 provides solid dosage forms of sparingly water-soluble pharmaceutical agents, i.e. solid or crystalline drugs having a water-solubility of 10 to 33 μg/ml at 25° C., such as glitazones. More particularly, this document discloses a pharmaceutical composition in the form of a solid particulate dispersion of such a pharmaceutical agent dispersed throughout a matrix of a water-soluble polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose. In a preferred embodiment, the particulate pharmaceutical agent is dispersed in the water-soluble polymer in a weight ratio of about 10% to about 90% active ingredient to about 90% to about 10% polymer. Other conventional excipients such as glycerin, propylene glycol, Tween, stearic acid salts and the like can be added.
U.S. Patent Publication No. 2001/0044409 discloses a process for the preparation of a poorly water soluble drug in solid dispersion comprising the steps of (a) blending the drug with a carrier, (b) dissolving a surfactant and a plasticizer/solubilizer in water, (c) spraying the surfactant-plasticizer/solubilizer solution onto the drug/carrier mixture in a fluid bed granulator, (d) extruding the resulting granulation through a twin screw extruder with at least one heating zone, and (e) milling the extrudate to a powdery mass of the solid drug dispersion. Within the scope of this process, said carrier may be selected from the group consisting of polyvinylpyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, acrylic polymers, succinic acid, sugars and mixtures thereof; the said plasticizer/solubilizer may be selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof, and the said surfactant may be selected from the group consisting of Tween, Span, Pluronics, polyoxyethylene sorbitol esters, monodiglycerides, polyoxyethylene acid polyoxyethylene alcohol and mixtures thereof. This process suffers from the disadvantage of providing a heating zone in the twin screw extruder and consequently a need for controlling and monitoring the temperature profile of the extruder for efficient quality control.
However, none of the above processes appear to be successful in formulating solid dosage forms of drugs having very low water-solubility, i.e. a solubility lower than 10 μg/ml, preferably lower than 5 μg/ml. This problem is applicable to a large number of drugs, including those belonging to the family of diamino-pyrimidines, such as stated in U.S. Pat. No. 6,211,185.
U.S. Pat. No. 3,639,637 discloses oestrogen compositions for the preparation of stable aqueous suspensions that can be sprayed onto animal feed, comprising (by weight) 70-95% of water-dispersible gel-forming microcrystalline cellulose and 5-30% of finely-divided diethylstilbestrol (a compound which is virtually insoluble in water) and optionally further up to one third of the weight of the composition of a hydrocolloid selected from the group consisting of sodium carboxy-methylcellulose, methylcellulose and hydroxyethylcellulose. The two latter cellulose compounds are known, namely from EP-A-403,383, to contribute to an extended linear drug release rate.
EP-A-352,190 discloses a solid pharmaceutical unit with a delayed dissolution of the active ingredient, i.e. allowing retention of the active ingredient and avoiding its complete and immediate availability by a simple contact with an aqueous liquid medium. It further discloses in example 9 paracetamol micro-granules obtained from a mixture of 182 g paracetamol (a drug belonging to class I of the Biopharmaceutical Classification System and having a water-solubility of 14 mg/ml), 728 g microcrystalline cellulose (AVICEL PH 101) and 90 g sodium carboxymethylcellulose. EP-A-352,190 however does not teach using a cyclodextrin compound as a drug dissolution enhancer.
U.S. Pat. No. 5,362,860 discloses (see table VI, example C) a composition with improved storage stability comprising (by weight) 0.05% of a pyridine based oxime (a drug undergoing hydrolysis into an aldehyde in an acidic environment), 70% cyclodextrin, 3% crosscarmellose (a crosslinked polymer) and 20.95% microcrystalline cellulose.
WO-A-99/12,524 solves the problem of drug formulations with both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time, by providing an oral modified release multiple-units composition wherein the unit dosage form comprises at least (i) a first fraction being able to release at least 50% of the drug within the first 20 minutes of a certain dissolution method, and (ii) a second fraction for delayed and extended release of the drug. The multiple-units of the first fraction may be granulates or, provided that a surfactant is added to the formulation, coated or uncoated pellets. Formulation of the first fraction depends on the specific drug but typically includes wet-granulation, and an antacid-like or other alkaline substance was found to have a pronounced increasing effect on the release rate.
U.S. Pat. No. 5,646,131 discloses (example 4) rapidly dissolving capsules containing a granulate formulation of a water-insoluble or sparingly soluble drug, such as terfenadine (less than 0.01 mg/ml water-solubility), surfactants (Tween 80 and sodium lauryl sulfate), cyclodextrin, Avicel PH 101 (microcrystalline cellulose) and a disintegrant/swelling agent (Primojel®, i.e. sodium carboxy-methyl starch) in a weight ratio of 10:72 to Avicel. These capsules provide better drug absorption, due to the presence of cyclodextrin, as evidenced by the figure showing a 90% drug release within 45 minutes.
Elbers et al. in Drug Development and Industrial Pharmacy (1992) 18(5):501-517 discloses theophylline pellets with a drug loading from 10 to 50% obtained by extrusion-spheronization with AVICEL 581 (a blend of microcrystalline cellulose and sodium carboxymethylcellulose). Theophylline is a drug with a water-solubility of 8 mg/ml (according to Merck Index, 12th edition 1996) and high permeability (according to FDA Guidance to Industry, 2000), thus belonging to class I of the Biopharmaceutical Classification System.
U.S. Pat. No. 4,235,892 discloses a series of 1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents including D-(threo)-1-p-methylsulfonyl phenyl-2-dichloroacetamido-3-fluoro-1-propanol, an antibacterial agent known as florfenicol and useful for veterinary purposes. Florfenicol has low solubility in water (about 1.3 mg/ml), as well as in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, and benzyl alcohol. For oral administration, these 1-aryl-2-acylamido-3-fluoro-1-propanol may be compounded in the form of tablets, or may even be admixed with animal feed. U.S. Pat. No. 4,235,892 therefore discloses making tablets by compressing granules of a composition comprising the said 1-aryl-2-acylamido-3-fluoro-1-propanol (in a drug loading range from 8.3% to 41.7% by weight), lactose, microcrystalline cellulose, starch and magnesium stearate.
The Biopharmaceutical Classification System (hereinafter referred as BCS) according to G. Amidon et al. in Pharm. Res. (1995) 12:413-420 provides for two classes of poorly soluble drugs, i.e. Class II and Class IV, and a class of highly soluble drugs, i.e. Class I. According to M. Martinez et al., Applying the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products (Part I: Biopharmaceutics and Formulation Consideration) in Advanced Drug Delivery Reviews (2002) 54:805-824, a drug substance should be classified as highly soluble when the highest dose strength is soluble in at most 250 ml of aqueous media over the pH range 1-7.5. In view of its water solubility (1.3 mg/ml) and of a maximal dose of 20 mg/kg for pigs, it is easy to calculate that the highest dose strength of florfenicol administered to pigs is soluble in an amount of water which is well above the limit value for the definition of a class 1 BCS highly soluble drug. Furthermore it is known from J. Voorspoels et al. in The Veterinary Record (October 1999) that florfenicol has a good oral bioavailability, so that it can be classified as a Class II compound as it is not a highly soluble drug and it shows no absorption problems.
U.S. Pat. No. 6,368,634 discloses a solid preparation suitable for a substantially immediate release of an active agent having a low or very low solubility, for example wherein more than 80% of the active agent is released within 2 hours, preferably within 1 hour or less from the administration. This solid preparation is obtained by pelletisation, i.e. an agglomeration process whereby fine powders or granules are shaped into fine, free-flowing units (pellets) with a particle size above 250 μm. The pellets of this solid preparation comprise one or more carriers (which may be polymers, or inorganic carriers such as talc, montmorillonite, bentonite, clay or calcium phosphate) and an active ingredient dissolved in a liquid phase (liquid as such or to be liquified for example by means of shear or temperature) which may be an oil or fat, a tensio-active agent or a polar co-solvent (such as polyethylene glycol, glycerol or propylene glycol). In U.S. Pat. No. 6,368,634 the active ingredient is dissolved in a liquid solubilizer (the weight ratio solubilizer/active agent being greater than 4) which is fixed on solid carrier particles preferably with a particle size below 500 μm such as microcrystalline cellulose, the resulting mixture being then transformed into pellets using a suitable batch technique such as extrusion/spheronisation, fluid-bed technology, rotary granulation. As a result the active ingredient is already in solution inside the dosage form (i.e. pellets) and hence is very quickly released from the dosage form upon contact with aqueous media. Therefore according to U.S. Pat. No. 6,368,634 it is essential to have a liquid phase in which the active ingredient can dissolve to obtain the reported dissolution profiles.
FIGS. 6 and 7 of U.S. Pat. No. 6,368,634 clearly illustrate that the active ingredient is no longer in its crystalline form inside the dosage form, but has gone into solution in the solubilizer. No peaks of crystalline hydrochlorothiazide (at 2θ=19°) are present in the X-ray diffraction pattern of pellets containing 3.5% by weight hydrochlorothiazide (HCT) and 32% by weight polyethylene glycol with a molecular weight of 400, as shown in FIGS. 6B and 6C. The importance of the active agent being dissolved in the liquid solubilizer is clearly shown in example 4 in combination with FIGS. 5 and 7 of U.S. Pat. No. 6,368,634. FIG. 5 shows a higher dissolution rate after 6 months storage of pellets containing 3.5% by weight HCT and 21% by weight polyethylene glycol hydrogenated castor oil. Immediately after preparation a crystalline peak of HCT was still visible (FIG. 7A), whereas it had disappeared after 6 months storage (FIG. 7B), i.e. all HCT crystals had dissolved, this behaviour being also indicative of a need for controlling drug formulation stability during storage. An increased dissolution rate was obtained after heat treatment of the pellets immediately after preparation, this again corresponding to the complete drug fraction going into solution as shown in FIG. 7C.
A limitation of the technology disclosed in U.S. Pat. No. 6,368,634 is that it only allows to increase the dissolution rate of formulations containing a low content of active ingredient (i.e. drug loading) since the amount of liquid phase (solubilizer) that can be fixed onto the solid carrier particles is limited to a weight ratio solubilizer/particles from 1:5 to 1:2, and the active ingredient further needs to dissolve into the solubilizer. This limitation is well illustrated in U.S. Pat. No. 6,368,634 teaching drug loadings in a range from about 1% by weight (examples 1 and 9) to about 6/% by weight (example 5). This limitation was confirmed by our experiments performed while preparing a pellet formulation based on the teachings of U.S. Pat. No. 6,368,634 but containing 20% by weight of a veterinary active ingredient. The release rate of this ingredient from the pellets was low and this slow drug release from the pellets was also reflected in low plasma levels of broiler chickens after administration of this formulation via drinking water.
Furthermore, U.S. Pat. No. 6,368,634 describes the dosage form as pellets which are produced by a suitable batch technique such as fluid-bed technology, rotary granulation or, preferably, extrusion-spheronisation. The extrusion-spheronisation process is a multi-step process capable of making uniformly sized preferably spherical particles (pellets). The following steps are required: (a) dry mixing, (b) wet granulation (i.e. formation of a wet mass, e.g. in U.S. Pat. No. 6,368,634 through the addition of a liquid phase and water (in order to get sufficient plasticity for extrusion), (c) extrusion (i.e. forming the wet mass into long rod-shaped particles), (d) spheronisation (breaking the rod-shaped particles into smaller pieces and rounding the individual particles into spheres) and (e) drying (removal of water added during granulation). Another limitation of the technology disclosed in U.S. Pat. No. 6,368,634 is thus that the stickiness of the wet mass formed in step (b) should not exceed a level where its extrusion in step (c) would become impossible and/or would block the extruder. This proviso implies significant limitations on the liquid solubilizer that may be used according to U.S. Pat. No. 6,368,634. In particular, the latter document does not teach or suggest the use of maltodextrins, and the skilled person knows that a mixture of water and a maltodextrin would have a stickiness much higher than permitted for extrusion. Another limitation of this technology is the need for an energy-consuming drying step in the final stage of the extrusion-spheronisation process.
Therefore, there is still a need in the art for formulating poorly soluble drugs classifiable as or belonging to Class II or Class IV of the Biopharmaceutical Classification System not only into formulations with low drug contents (such as known from U.S. Pat. No. 6,368,634) but also into formulations with moderate and even high drug contents. There is also a need in the art for making formulations of poorly soluble drugs classifiable as or belonging to Class II or Class IV of the Biopharma-ceutical Classification System by means of a continuous production method, not a batch-wise production method, in order to decrease their production cost. There is also a need in the art for making formulations of poorly soluble drugs classifiable as or belonging to Class II or Class IV of the Biopharma-ceutical Classification System by an energy-saving production method which does not require a drying step, in order to decrease their production cost. There is also a need in the art for formulating poorly soluble drugs classifiable as or belonging to Class II or Class IV of the Biopharmaceutical Classification System as granules, not pellets. There is also a need in the art for formulating poorly soluble drugs classifiable as or belonging to Class II or Class IV of the Biopharma-ceutical Classification System in the absence of a costly pharmaceutical grade material such as microcrystalline cellulose.
There is a specific need in the art to provide a solid formulation of drugs with a water-solubility like florfenicol or lower. Florfenicol is a drug for administration to warm-blooded animals, such as cattle with naturally-occurring bovine respiratory disease, swine, sheep, goats and poultry, which at present is mainly available in the form of injectable solutions. Until now the skilled person has failed in the design of such a solid formulation of florfenicol, which can further be admixed with animal feed if necessary. There is therefore a need in the art for a florfenicol formulation in the form of a water-soluble granulate for administration to animals together with drinking water. Also there is a need for a solid formulation for many low solubility drugs for human and veterinary therapies.